The goal of this study is to exploit the genetic variance between MOLF/EiJ and C57BL/6 mice to discover novel genes or polymorphic alleles that modify immune responses to intracellular viral and bacterial infections. Understanding the influence of allelic inheritance on immune responses is essential to understanding differences in susceptibility to disease in the genetically diverse human population. Using forward genetics we have found multiple loci linked with differences in cytokine responses between these two murine sub species. One locus contained a naturally occurring loss-of-function Tmem173 allele in MOLF/EiJ mice that confers a lack of interferon response to cytosolic DNA and c-di-AMP. In Aim 1, my investigation into how these novel polymorphisms abrogate interferon signaling will lead to a deeper understanding of how this signaling pathway works. Furthermore, these mice will be used to generate a live infection model, in Aim 2, to relate the importance of the human loss-of-function allele (HAQ) in susceptibility to diseases caused by intracellular pathogens such as Listeria Monocytogenes, Mycobacterium tuberculosis, and Herpes viruses. In this study, other loci have been found to contribute to this differential immune response of MOLF/EiJ mice to cytosolic DNA and c-di-AMP. Further mapping proposed in my project, in Aim 1, can lead to the discovery of novel genes important in cellular-mediated immunity.